In a 2018 article in the journal The Lancet, researchers led by Andrea Cipriani compared the efficacy of 21 different antidepressants and established that antidepressants are more effective than placebo at reducing unipolar depression. To date, this is the largest meta-analysis of double-blind, randomized controlled studies of antidepressant efficacy, including 522 trials and a total of 116,477 participants. All 21 of the antidepressants were found to be more effective than placebo.

Looking at head to head studies, Cipriani and colleagues found that the most effective antidepressants were agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine. The least effective antidepressants were fluoxetine, fluvoxamine, reboxetine, and trazodone.

In terms of tolerability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were most tolerable to patients, while amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine caused the most study dropouts due to side effects. Only agomelatine and fluoxetine had better dropout rates than placebo.

Interestingly, agomelatine, the medication found to be most effective and most tolerable, is unavailable in the US. Pharmaceutical company Novartis, which owns the rights to the drug, was disappointed by some lackluster studies of the drug and never applied for Food and Drug Administration approval to sell it in the US. The studies found potential problems regarding drug interactions related to the metabolic enzyme CYP1A2 and a risk of liver damage with longer-term use.

Editor’s Note: This meta-analysis should end any remaining controversy about the efficacy of antidepressants in the acute treatment of unipolar depression.

This study did not address maintenance treatment for the prevention of depressive episodes. Researcher John R. Geddes and colleagues have found robust, statistically significant data that continuation treatment with antidepressants can prevent depressive relapse, suggesting that if patients continue taking effective antidepressants, rather than switching to placebo, the antidepressants can reduce depressive occurrences by about 70%.

It is now recommended in most guidelines that patients with two or three prior episodes of depression consider staying on antidepressants indefinitely over their lifetime in order to prevent recurrence. Antidepressants increase the creation of new neurons and brain-derived neurotrophic factor (BDNF), which protects neurons and is important for learning and memory. Antidepressants can also prevent loss of hippocampal volume.

A 2017 article by Vanda Faria and colleagues in the journal EBioMedicine reports that when patients with social anxiety disorder were told they were being treated with an active drug, they had a response rate three times higher than patients who were given the same drug but told it was an inactive placebo. The researchers suggest that the way treatments are presented to patients affects whether they work.

In the study by Faria and colleagues, patients with social anxiety were given the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram for nine weeks. Some were told they had received escitalopram, while some were told they had received a placebo. Not only did those who were told they were taking escitalopram see greater reductions in their anxiety, they also showed more connectivity between the posterior cingulate and the amygdala, a region that is crucial to mediating anxiety.

This finding is in line with other research that has found that patients’ thoughts and expectations during treatment can affect the efficacy of that treatment.

Researcher Isaac Marks found that patients with obsessive compulsive disorder (OCD) with fear of contamination who were told to avoid things they feared, such as touching a toilet seat, did not fare any better than those taking placebo pills. However, those taking SSRIs who tried new behaviors like touching a toilet seat learned that they could do so without a major fear response, and their phobias improved.

Several studies have shown that expectations of antidepressant efficacy have a big effect on whether patients with unipolar depression improve after beginning treatment with SSRIs. Bret R. Rutherford and colleagues reviewed findings on expectancy in major depressive disorder in a 2010 article in the journal Current Psychiatry Review.

When patients are presented with a drug and encouraged to believe it will work, they may gain the confidence to try out new behaviors or ways of looking at things, whether that means exploring new social situations for someone with social anxiety, or feeling hopeful and breaking the habit of negative rumination for someone with depression. As the study by Faria and colleagues shows, expectations can even change patterns of brain connectivity.

Studies of repetitive transcranial magnetic stimulation (rTMS), in which electromagnets placed near the scalp stimulate electrical impulses in the brain, have shown that patients with depression who engage in positive thoughts and conversations with their rTMS provider during the stimulation improve more than those who sit passively. If a patient engages in their habitual negative ruminations during rTMS, these might even be cemented by the rTMS-induced release of glutamate and brain-derived neurotrophic factor (BDNF), which are both involved in learning and memory processes and what has been called experience-dependent neuroplasticity.

Thus, a patient’s thoughts and outlook during treatment may be important to the therapeutic outcomes achieved. While expectations may not be sufficient to produce an effect on their own, it does seem that thoughts and behaviors can improve a treatment’s efficacy.

Although the editors of BipolarNews.org have made every effort to report accurate information, much of the work referenced here is in abstract or pre-publication form, and may not have received proper review by the scientific community at this time. Patients should consult with their physicians about any treatment decisions. Physicians should consult the peer-reviewed literature.